1,4-bis(ethoxymethyl)cyclohexane is a known fragrance chemical exhibiting favorable organoleptical properties, in particular a pleasant odor. 1,4-bis(ethoxymethyl)cyclohexane is therefore of great interest as fragrance for example in the field of cosmetics or in the field of laundry and cleaning detergents.
There is a demand for novel processes that allow the efficient production of 1,4-bis(ethoxymethyl)cyclohexane, e.g. by making use of mild reaction conditions to improve the yield and reduce the formation of unwanted by-products.
The synthesis of mono and di-ethers of 1,4-bis(hydroxymethyl)cyclohexane, including 1,4-bis(ethoxymethyl)cyclohexane, was frequently described in the art.
JP-11035969 A for example describes 4-(alkoxymethyl)-1-(hydroxymethyl)-cyclohexanes and a process for their preparation, which comprises the reaction of 1,4-bis(hydroxymethyl)cyclohexane with an alkyl, cycloalkyl or alkenyl halide in the presence of a base, in particular sodium hydride, and a solvent, in particular THF.
JP-11029512 A describes 4-(alkoxymethyl)-1-(hydroxymethyl)cyclohexanes and a process for their preparation, which comprises either the reaction of 1,4-bis(hydroxymethyl)cyclohexane with an alkyl, cycloalkyl or alkenyl halide in the presence of a base, in particular sodium hydride in THF, or the reaction of 1,4-bis(hydroxymethyl)cyclohexane with an olefin in the presence of a strong acid, in particular sulfuric acid in combination with boron trifluoride ether complex.
Solladie et al., Journal of Organic Chemistry, 1985, Vol. 50(21), pp. 4062-4068, for example describe a process for the production of 1,4-bis(ethoxymethyl)cyclohexane, which comprises the reaction of 1,4-bis(hydroxymethyl)cyclohexane with ethyl iodide in the presence of sodium hydride in THF. The alkylation reaction is performed under reflux for 16 hours to yield 30% of 4-(ethoxymethyl)-1-(hydroxymethyl)cyclohexane and 32% of 1,4-bis(ethoxymethyl)cyclohexane.
WO 2013/4579 A2 describes a process for the synthesis of 1,4-bis(ethoxymethyl)cyclohexane, which comprises the reaction of 1,4-bis(hydroxymethyl)cyclohexane in the presence of potassium hydroxide with acetylene followed by the catalytic hydrogenation of the thus obtained di-vinyl ether with hydrogen in the presence of a hydrogenation catalyst.
Freedman et al., Tetrahedron Letters, 1975, No. 38, pp. 3251-3254, for example describe the preparation of ethers from sterically less demanding mono-alcohols as well as from sterically less demanding 1,4-butandiol by reacting them with an excess of primary alkyl chlorides or benzyl chloride in the presence of an 50% aqueous sodium hydroxide solution and 3-5 mol-% of tetrabutylammonium bisulphate as phase transfer catalyst. Alkylation of sterically demanding —CH2—OH groups bound to cycloaliphatic moieties were not described.
It is apparent form the state of the art, that the preparation of di-ethers of 1,4-bis(hydroxymethyl)cyclohexane is challenging. The known synthetic processes, which aim for the production of 1,4-bis(ethoxymethyl)cyclohexane through the direct alkylation of 1,4-bis(hydroxymethyl)cyclohexane, typically require highly reactive and expensive bases, such as sodium hydride, and/or suffer from moderate yields, since the alkylation reactions do often not proceed to completion, resulting in the formation of significant amounts of the mono-ether species. If harsh reaction conditions are applied, e.g. reaction conditions used in classical ether synthesis, in order to improve the yield of the di-ether species, the formation of unwanted by-products, which may have malodorous properties, is often increased.